Protecting Brain Cells from Stroke

Every year, nearly 800,000 Americans suffer a stroke and almost 130,000 die. Survivors often are left with long-term physical and cognitive disabilities that significantly alter their lives.

Currently there are limited treatments for acute stroke that make a
real difference in patient's lives. There is an urgent need to
identify, test, and translate new therapies to the clinic.

Researchers from the University of Iowa Carver College of Medicine
and the University of Miami Miller School of Medicine have shown that a
neuroprotective compound tested in rats provides two-pronged protection
for brain cells during stroke and improves physical and cognitive
outcomes in the treated animals.

‘P7C3 compound protects mature and newborn neurons in rats, and also improves physical and cognitive outcomes, following stroke.’

When a stroke interrupts the brain's blood supply, mature brain
cells (neurons) die. In addition, reestablishing blood flow, known as
reperfusion, also leads to processes that cause cell death. A part of
the brain's natural response to stroke injury is to increase production
of new brain cells in two specific regions (the subgranular zone of the
hippocampal dentate gyrus and the subventricular zone of the lateral
ventricles), which normally make a smaller number of new brain cells
every day. Unfortunately, the vast majority of these newborn cells die
within one to two weeks, limiting the benefit of this potential repair
process. Minimizing the loss of brain cells is a primary goal for new
stroke therapies.

"If we could prevent the mature brain cells from dying that would be
beneficial," says Andrew Pieper, professor of psychiatry in
the UI Carver College of Medicine and co-senior study author. "But if we
could also support or enhance this surge in neurogenesis (birth of new
neurons), we might be able to further foster recovery, especially in
terms of cognitive function, which is critically dependent on the
hippocampus."

Using rats, Pieper and his colleagues Zachary B. Loris and W. Dalton
Dietrich, tested the effects of a compound called P7C3-A20 on
these two aspects of neuroprotection following ischemic stroke. Blood
flow to the rats' brains was interrupted for 90 minutes and then the
blockage was cleared allowing reperfusion. One group of rats was given
the P7C3-A20 compound twice daily for seven days following the stroke.
P7C3-A20 has previously been shown to prevent brain cell death in other
animal models of neurologic injury, including Parkinson's disease,
amyotrophic lateral sclerosis, stress-associated depression, and
traumatic brain injury.

In terms of the brain itself, the P7C3-A20 compound reduced loss of
brain tissue (atrophy) and increased survival of newborn neurons six
weeks after stroke. In addition to the improved survival of both mature
and newborn neurons, rats that received the P7C3-A20 compound for seven
days after stroke also had better physical and cognitive outcomes than
untreated rats. Treated rats had improved balance and coordination one
week after stroke, and improved learning and memory one month after
stroke. The findings were published recently in the journal Experimental Neurology.

"There is no previous demonstration of a pharmacologic agent that
both protects mature neurons from dying and also boosts the net
magnitude of neurogenesis," Pieper says. "Our compound is beneficial in
this animal model of stroke, and we're hopeful that it might eventually
benefit patients."

Dietrich, co-senior study author and Scientific Director of The Miami
Project to Cure Paralysis, professor of neurological surgery, neurology,
biomedical engineering and cell biology at the University of Miami
where the studies were conducted, said, "The ability to both protect and
repair the injured nervous system has major implications on how we think
about improving outcomes in millions of people each year with acute
neurological injuries."

The neuronal protection provided by the P7C3-A20 compound was also
associated with a boost in the levels of a substance called nicotinamide
adenine dinucleotide (NAD) in the rats' brains. NAD is emerging as an
important player in neuronal health and survival. Levels of this
substance are depleted during stroke, and it has been proposed that
increasing NAD levels may be a therapeutic target for treating stroke.
In this study, P7C3-A20 treatment restored NAD to normal levels in the
rats' cortex after a stroke.

Importantly, the study examined the effects of P7C3-A20 on cognitive
and physical outcomes well beyond the time of the initial stroke. The
sustained physical and cognitive improvement seen in the rats up to one
month after the stroke suggests that the P7C3-A20 compound provides a
long-term benefit.

"We found we can give the compound in this critical period
immediately after the stroke and it has a lasting effect," notes Pieper,
who also is a professor of neurology, radiation oncology, and a
psychiatrist with the Iowa City Veterans Affairs Health Care System.

In recent years, advances in treatments that break up or remove
stroke-causing blood clots have reduced the death rate for stroke and
are improving outcomes for patients. The researchers hope that a
treatment based on P7C3-A20 used in addition to the clot-clearing
therapies might further improve outcomes by protecting brain cells
during the traumatic ischemia/reperfusion period.

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